ES2246488T3 - REBOXETINE TO TREAT MIGRAINE. - Google Patents

Abstract

The use of racemic reboxetine, or one of its pharmaceutically acceptable salts, in the manufacture of a non-transdermal drug for the treatment or prophylaxis of migraines.

Description

Reboxetine to treat migraine.

Background of the invention Field of the Invention

The present invention relates to the use of racemic reboxetine or one of its pharmaceutically acceptable salts in the preparation of a non-transdermal medicine for treatment or prophylaxis of migraines.

Brief description of the technology related

Many types of depression disorders, Mental, behavioral, and neurological originate from alterations in brain circuits that transmit signals using certain monoamine neurotransmitters. Neurotransmitters Monoamine include, for example, norepinephrine (norepinephrine), serotonin (5-HT), and dopamine. Levels lower than Normal norepinephrine are associated with various symptoms that They include lack of energy, motivation, and interest in life. From In this way, a normal level of norepinephrine is essential for maintain dynamism and the ability to feel satisfaction.

These neurotransmitters travel from the end of a neuron through a small gap (that is, the synaptic cleft) and bind to receptor molecules on the surface of a second neuron. This union causes intracellular changes that initiate or activate a response or change in the postsynaptic neuron. Inactivation is mainly caused by the transport (i.e. reuptake) of the neurotransmitter in the presynaptic neuron. The abnormality in noradrenergic transmission results in various types of depression, mental, behavioral, and neurological disorders attributed to various symptoms that include lack of energy, motivation, and interest in life. See generally , RJ Baldessarini, "Drugs and the Treatment of Psychiatric Disorders: Depression and Mania" in Goodman and Gilman's The Pharmacological Basis of Therapeutics , McGraw-Hill, New York, pages 432-439 (1996).

Reboxetine (i.e. 2 - [(2-ethoxyphenoxy) (phenyl) methyl] morpholine) raises the concentration of physiologically active norepinephrine, preventing, for example, the reuptake of norepinephrine. Reboxetine is a norepinephrine reuptake inhibitor and has proven effective in the short term (i.e., in less than eight weeks) and in the long-term treatment of depression. In fact, reboxetine has been shown to have an efficacy that is similar to fluoxetine, imipramine, and desipramine, commonly prescribed antidepressants, in both adult and elderly patients. See SA Montgomery, Reboxetine: Additional Benefits to the Depressed Patient , Psychopharmacol (Oxf) 11: 4 Suppl., S9-15 (Summary) (1997).

Antidepressant drugs are sometimes divided into "generations." The first generation included monoamine oxidase inhibitors (such as isocarboxazide and phenylhydrazine) and tricyclic agents (such as imipramine). The second generation of antidepressant drugs included compounds such as mianserin and trazodone. The third generation has included drugs called selective reuptake inhibitors (for example, fluoxetine, sertraline, paroxetine, and reboxetine). These drugs were characterized by the relatively selective action on only one of the three major monoamine systems that were thought to be involved in depression (i.e., 5-HT (serotonin), norepinephrine (norepinephrine), and dopamine). APP Textbook of Psychopharmacology (AF Schatzberg and CB Nemeroff), American Psychiatric Press, 2nd ed., (1998); Lexicon of Psychiatry, Neurology and the Neurosciences (FJ Ayd, Jr.) Williams and Wilkins (1995). The antidepressant efficacy of reboxetine is demonstrated by its ability to prevent resperine-induced blepharospasms and hypothermia in mice, down-regulation of β-adrenergic receptors and desensitization of noradrenaline-coupled adenylate cyclase. See M. Brunello and G. Racagni, "Rationale for the Development of Noradrenaline Reuptake Inhibitors", Human Psychopharmacology, vol. 13, S- 13-519, Suppl. 13-519 (1998).

According to a study by Brian E. Leonard, desipramine, maprotiline, and lofepramine are relatively selective norepinephrine reuptake inhibitors with proven efficacy. These substances increase cerebral norepinephrine and thus work by relieving depression. Mianserine and mirtazepine also show similar antidepressant effects by increasing the availability of norepinephrine by blocking the presynaptic α2-adrenoceptors. Furthermore, oxaprotiline, phezolamine, and tomoxetine are potent and selective norepinephrine reuptake inhibitors that lack neurotransmitter receptor interactions and, thus, do not cause many of the characteristic side effects of tricyclic antidepressants. traditional. See Brian E. Leonard, "The Role of Noradrenaline in Depression: A Review", Journal of Psychopharmacology, vol. 11, No. 4 (Suppl.), Pages S39-S47 (1997).

Reboxetine is also a selective norepinephrine reuptake inhibitor, which also produces less of the side effects associated with the administration of traditional tricyclic antidepressants. The antidepressant efficacy of reboxetine is demonstrated by its ability to prevent resperine-induced blepharospasms and hypothermia in mice, down-regulation of β-adrenergic receptors and desensitization of noradrenaline-coupled adenylate cyclase. See M. Brunello and G. Racagni, "Rationale for the Development of Noradrenaline Reuptake Inhibitors", Human Psychopharmacology, vol. 13, (Suppl.) 13-519 (1998).

Reboxetine is generally described in Melloni et al ., U.S. Pat. Nos. 4,229,449, 5,068,433 and 5,391,735, and in GB-A-2,167,407. Chemically, reboxetine has two chiral centers and, therefore, exists as two enantiomeric pairs of diastereomers, which are shown below as isomers (I) to (IV):

one

(R, R) 2 - [(2-ethoxyphenoxy) (phenyl) methyl] morpholine

2

(H.H) 2 - [(2-ethoxyphenoxy) (phenyl) methyl] morpholine

3

(R, S) 2 - [(2-ethoxyphenoxy) (phenyl) methyl] morpholine

4

       \ vskip1.000000 \ baselineskip
    

(MR) 2 - [(2-ethoxyphenoxy) (phenyl) methyl] morpholine

Many organic compounds exist in forms optically active, that is, they have the ability to rotate the Polarized light plane. Describing a compound optically active prefixes R and S are used to indicate the configuration absolute of the molecule with respect to its center (s) chiral (s). The prefixes D and L, or (+) and (-), indicate the sign in which the compound rotates the plane of light polarized, L or (-) means that the compound is levógiro. TO difference of a compound with the prefix D or (+) which is dextro-rotatory. There is no correlation between the nomenclature for the absolute stereochemistry and for the rotation of an enantiomer. So, D-lactic acid is the same as acid (-) - lactic and L-lactic acid is the same as (+) - lactic acid. For one given chemical structure, each pair of enantiomers are identical, except that the mirror image of one is not superimposable with the of the other. A specific stereoisomer can also be called enantiomer, and a mixture of such isomers is called with mix, enantiomeric or racemic frequency.

Stereochemical purity is important in the pharmaceutical field, in which many of the drugs prescribed with more frequently show chirality. For example, the L enantiomer of the beta-adrenergic blocking agent, the propanolol, it is known to be 100 times more potent than its enantiomer D. Additionally, optical purity is important in the field pharmacist because it has been discovered that certain isomers cause more a harmful effect than beneficial or inert. For example, it is believed that the thalidomide D enantiomer is a safe and effective sedative when prescribed for dizziness control during pregnancy, while its corresponding enantiomer L is believed to be a powerful teratogen.

When there are two chiral centers in one molecule, there are four possible stereoisomers: (R, R), (S, S), (R, S) and (MR). Of these, (R, R) and (S, S) are an example of a pair of enantiomers (mirror images of each other), which as a rule generally share chemical properties and melting points as any other pair of enantiomers. The mirror images of (R, R) and (S, S) are not, however, superimposable with (R, S) and (S, R). This relationship is called diastereoisomer, and the molecule (S, S) is a diastereomer of the molecule (R, S), while the molecule (R, R) is a diastereomer of the molecule (S, R).

Currently, reboxetine is available commercially only as a racemic mixture of enantiomers, (R, R) and (S, S) in a 1: 1 ratio, and the references herein memory to the generic name "reboxetine" refer to this mixture, enantiomeric or racemic. Reboxetine is sold commercially with the trade names of EDRONAX®, PROLIFT®, VESTRA®, and NOREBOX®. As previously indicated, reboxetine It has proven useful in the treatment of depression in Humans. Reboxetine administered orally is absorbed easily and requires administration once or twice a day. A Preferred daily dose for an adult is in the range of about 8 to about 10 milligrams (mg). The dose effective daily reboxetine for a child is less, as a rule general in the range of about 4 to about 5 mg. However, the optimal daily dose for each patient should be determined by a deputy doctor taking into account the size of the patient, other medications that the patient may be taking and the identification and severity of the particular disorder, and all Other circumstances of the patient.

It has been reported that other antidepressants have a high pharmacological selectivity to inhibit the reuptake of norepinephrine. For example, oxaprotiline has a pharmacological selectivity with respect to inhibiting the reuptake of norepinephrine compared to the reuptake of serotonin of approximately 4166, based on a ratio of Ki values. The corresponding pharmacological selectivity for desipramine is approximately 377, and that of maprotiline is approximately 446. See Elliot Richelson and Michael Pfenning, "Blockade by Antidepressants and Related Compounds of Biogenic Amine Uptake in Rat Brain Synaptosomes: Most Antidepressants Selectively Block Norepinephrine Uptake" , European Journal of Pharmacology, vol. 14, pages 277-286 (1984). Despite the relatively high selectivity of oxaprotiline, desipramine, and maprotiline, these and other known substances undesirably block the receptor of other neurotransmitters to a sufficient extent that also contribute to adverse side effects.

WO international patent application 00/00120, which was published after the priority dates of this application, but before the filing date, describes a transdermal formulation suitable for treatment of pain in an individual. The transdermal formulation includes a compound containing an amine, such as racemic reboxetine.

There is a need for medications for treatment or prophylaxis of migraines containing reboxetine racemic, and the use of racemic reboxetine in the manufacture of such medications.

Compendium of the invention

The present invention is directed to the use of racemic reboxetine or one of its pharmaceutically active salts acceptable, in the manufacture of a non-transdermal drug for the treatment or prophylaxis of migraines.

Additional benefits and features of the The present invention will be apparent to those skilled in the technique from a review of the following description detailed, taken together with the example and the claims attached.

Detailed description of the preferred embodiments

Reboxetine is a known compound that is active in the central nervous system, and has been used as antidepressant Until now, the use of reboxetine has been limited to the treatment of depression, of the disorder of the oppositional and challenging behavior of deficiency disorder in attention / hyperactivity, and behavioral disorder. These proposed treatments are described in the publications International Nos. WO 99/15163, WO 99/15176, and WO 99/15177. These treatment methods are limited to the administration of a racemic mixture of the stereoisomers (S, S) and (R, R) of the reboxetine

Reboxetine does not act like most antidepressants. Unlike tricyclic antidepressants, and even selective serotonin reuptake inhibitors (SSRIs), reboxetine is ineffective in the hypothermia 8-OH-DPAT test, indicating that reboxetine is not an SSRI. Brian E. Leonard, "Noradrenaline in basic models of depression". European-Neuropsychopharmacol, 7 Suppl. 1, pages S11-6 and S71-3 (April 1997). Reboxetine is a selective norepinephrine reuptake inhibitor, with marginal serotonin reuptake inhibitory activity and no dopamine reuptake inhibitory activity. Reboxetine shows no anticholinergic binding activity in different animal models, and is basically devoid of monoamine oxidase (MAO) inhibitory activity. Racemic reboxetine shows a pharmacological selectivity of serotonin (Ki) / norepinephrine (Ki) of approximately 80. Ki values are discussed in more detail below.

As used herein, the term "reboxetine" refers to the racemic mixture of enantiomers (R, R) and (S, S) of reboxetine. Unlike the terminology "reboxetine (S, S)" which refers only to stereoisomer (S, S). Similarly, the terminology "reboxetine (R, R)" refers only to the stereoisomer (R, R).

The phrases "pharmacologically salts acceptable "or" one of its pharmacologically salts acceptable "refers to salts prepared from acids or pharmacologically acceptable bases, including acids and bases Organic and inorganic. Because the active compound (that is, racemic reboxetine) used in the present invention is basic, salts can be prepared from pharmaceutically acidic acceptable. Suitable pharmaceutically acceptable acids include acetic, benzenesulfonic (besylate), benzoic, p-bromophenylsulfonic, canphosulfonic, carbonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, hydroiodic, isethionic, lactic, maleic, Malic, Mandelic, Methanesulfonic (Mesylate), Mucus, Nitric, oxalic, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic and the like. So, examples of said pharmaceutically acceptable reboxetine salts racemic include acetate, benzoate, β-hydroxybutyrate, bisulfate, bisulfite, bromide, butin-1,4-dioate, caproate, chloride, chlorobenzoate, citrate, dihydrogen phosphate, Dinitrobenzoate, fumarate, glycolate, haptanoate, hexin-1,6-dioate, hydroxybenzoate, iodide, lactate, maleate, malonate, mandelate, metaphosphate, matanesulfonate, methoxybenzoate, methylbenzoate, monohydrogen phosphate, naphthalen-1-sulfonate, naphthalen-2-sulfonate, oxalate, phenylbutyrate, phenylpropionate, phosphate, phthalate, phenylacetate, Propanesulfonate, Propriolate, Propionate, Pyrophosphate, Pyrosulfate, sebacate, suberate, succinate, sulfate, sulphite, sulphonate, tartrate, xylenesulfonate, and the like. A pharmaceutical salt Preferred racemic reboxetine is methanesulfonate (i.e. mesylate), which is prepared using methanesulfonic acid.

As used herein, the terms "treat", "treatment" and "trying", refer to: (a) prevent the onset of a disease, disorder or condition in a human being who may be predisposed to disease, disorder and / or medical condition but who has not yet been diagnosed who suffers from it; (b) inhibit the disease, disorder or ailment, that is, stop its development; and (c) mitigate the disease, disorder or medical condition, that is, causing regression of the  disease, disorder and / or medical condition In other words, the terms "treat", "treatment" and "trying" extend to prophylaxis, in other words "prevent", "prevention" and "preventing" as well as the treatment of ailments ingrained Therefore, the use of the terms "prevent", "prevention" and "preventing" would be a administration of the pharmaceutical composition to a person who has suffered in the past from migraines, but who is not suffering from ailments at the time of administration of the composition. In name of simplicity, the term "ailments" as used of From now on it covers ailments, diseases and disorders.

According to the present invention, reboxetine racemic is useful for treating migraines in which to inhibit the Norepinephrine reuptake provides a benefit. The racemic reboxetine can be administered, and administered preferably orally, in an amount sufficient to provide a total dose of 0.1 to 10 mg / day of the compound at a individual.

Racemic reboxetine or one of its salts Pharmaceutically acceptable can be used to treat migraines. In addition, racemic reboxetine or a pharmaceutically active salt thereof. acceptable can be used to treat headaches in migraines or people suffering from migraines, including treatment of the symptoms of an existing headache, treatment to avoid the appearance, intensity, and duration of a headache, prophylactic use to avoid or reduce incidence or duration of migraines, as an adjuvant for facilitate the efficacy of a medicine or be administered together with other medications to reduce the required doses (and effects side effects) of those medications.

The synthesis of a racemic mixture of reboxetine is described in Melloni et al . U.S. Patent No. 4,229,449.

Although it is possible to administer racemic reboxetine or one of its pharmaceutically acceptable salts directly without no formulation, a composition is preferably administered in the form of pharmaceutical drugs comprising reboxetine racemic or one of its pharmaceutically acceptable salts. The composition of the invention can be administered in forms of Unit dosage orally as tablets, capsules, pills, powder or granules. The composition of the invention. it can also be administered parenterally, (for example of subcutaneous, intravenous, or intramuscular form), using forms known in the pharmaceutical art. The composition of the invention. it can also be administered rectally or vaginally in such ways as ovules or suppositories.

It may be desirable or necessary to administer the pharmaceutical composition or compositions containing the inhibitor selective norepinephrine reuptake in the brain, since either directly or indirectly. Direct techniques usually involve the placement of a catheter suitable for administration of the drug in the ventricular system to derive the barrier blood brain One such suitable management system used to transport biological factors to anatomical areas Specific body is described in US Pat. nº 5,011,472.

In general, the preferred route to administer the Composition is orally, with administration once or twice at day. The regimen and dosage amount to treat patients with the composition is selected according to various factors that include, for example, the type, age, weight, sex and medical situation of the patient, the severity of the condition, the route of administration and the particular compound employed by reboxetine racemate. A generally skilled doctor or psychiatrist can determine and easily prescribe an effective amount (i.e. therapeutic) of the compound to prevent or stop the progression of the ailment. Proceeding like this, the doctor or psychiatrist could use doses relatively low at first, subsequently increasing the dose until a maximum response is obtained.

Pharmaceutical compositions suitable for oral administration can be anyway convenient, such as sachets, tablets, capsules, pills, or aerosol sprayers, each containing an amount default of the active compound either powdered or granulated, or as a solution or a suspension in an aqueous liquid, a non-aqueous liquid, an oil-in-water emulsion, or an emulsion of Water liquid in oil. Such compositions can be prepared by any method that includes the step of carrying the active compound in intimate association with a vehicle, which constitutes one or more Necessary or desirable ingredients. Generally the compositions They are prepared by mixing together in a uniform and intimate way active ingredient with liquid vehicles or solid vehicles finely divided or both, and then, if necessary, giving the Product the desired way.

For example, a tablet can be prepared by compression or molding techniques using, optionally, one or more secondary ingredient Compressed tablets can be prepared by compressing the active ingredient in a machine appropriate in a free form, such as powder or granules. After this, the free, compressed form can optionally be mixed with aggregators, diluents, lubricants, disintegrating agents, agents of effervescence, colorants, sweeteners, wetting agents, and non-toxic and pharmacologically inactive substances present by general rule in pharmaceutical compositions. The tablets molded can be made by molding a mixture of the powder compound moistened with an inert diluent liquid in a machine appropriate.

Aggregators suitable for use in the preparation Pharmaceutical include, for example, starches, gelatin, methylcellulose, gum arabic, tragacanth, and polyvinylpyrrolidone. Diluents suitable for use in pharmaceutical preparation include, for example, lactose, dextrose, sucrose, mannitol, sorbitol, and cellulose. Lubricants suitable for use in the Pharmaceutical preparation include, for example, silica, talc, acid  stearic, magnesium or calcium stearate, and or polyethylene glycols. Disintegrating agents suitable for use in the preparation Pharmaceuticals include, for example, starches, alginic acid, and alginates Wetting agents suitable for use in the preparation Pharmaceutical include, for example, lecithin, polysorbates, and lauryl sulfates In general, any effervescence agent, dyes and / or sweeteners known to those skilled in the technique can be used in the preparation of a composition Pharmaceutical

According to the present invention, reboxetine racemic is effective in the treatment of children patients, teenagers and adults For the purpose of the present invention, a child is considered to be a person below the age of the puberty, a teenager is considered to be a person among the age of puberty and up to approximately 18 years of age, and a adult is usually a person of at least about 18 year old. As previously indicated, the daily dose optimal for each patient should be determined by an assistant doctor taking into account the size of each patient, other medications that the patient is taking, identification and severity of the medical condition, and all other circumstances of the patient.

As indicated above, reboxetine acts as an antidepressant. Reboxetine, however, does not act like most antidepressants. Unlike tricyclic antidepressants, and even selective serotonin reuptake inhibitors (SSRIs), reboxetine is ineffective in the hypothermia 8-OH-DPAT test, indicating that reboxetine is not a selective inhibitor of Serotonin reuptake. Instead, reboxetine is selective for the noradrenergic system. Reboxetine is not an SSRI, but it is a novel, selective norepinephrine reuptake inhibitor (NRI). B. Leonard, "Noradrenaline in basic models of depression". European-Neuropsychopharmacol, 7 Suppl. 1, pages S11-6 and S71-3 (April 1997). Unlike most drugs from previous generations, reboxetine is a highly selective norepinephrine reuptake inhibitor, with only marginal serotonin reuptake inhibitory activity and no dopamine reuptake inhibitory activity. Reboxetine shows no anticholinergic binding activity in different animal models, and is devoid of monoamine oxidase (MAO) inhibitory activity.

Reboxetine is also an extremely active agent. powerful, pharmacologically specific and that acts fast. The research indicates that reboxetine has potent activity antireserpine, and combines the inhibitory properties of traditional tricyclic antidepressants in the reuptake of the norepinephrine with a capacity to desensitize the function of β-adrenergic receptor, without showing any appreciable blocking action in muscarinic receptors, cholinergic, histaminergic and α-adrenergic. In addition, reboxetine shows less vagolytic activity than tricyclic antidepressants, and not shows evidence of cardiotoxicity.

According to the present invention, reboxetine Racemic can be used to treat or prevent migraines. Specifically, it has been discovered that reboxetine is especially useful for treating or improving treatment or prevention migraines, more effectively and with less effect secondary than with treatment with known drugs.

Mental and neurological disorders that are can treat or prevent by administering an amount therapeutically effective of a racemic reboxetine (or one of its pharmaceutically acceptable salts) according to the present invention They understand migraines.

Racemic reboxetine can be used to treat to humans suffering from migraines, especially to reduce the frequency, duration, intensity, and or complications that result of migraines. In addition, racemic reboxetine can be used to Avoid migraines.

The racemate form of reboxetine is fine tolerated and has a wide safety interval. Reboxetine racemic can be administered to an individual in an amount in the range of 2 to 20 milligrams per patient per day (mg / day), and preferably 4 to 10 mg / day, and more preferably 6 to 10 mg / day Depending on the formulation and disorder of the individual, the total daily dose can be administered in small amounts Up to twice a day. Reboxetine is administered as a rule general orally, for example, in the form of tablets, but It can be administered parenterally, rectally or vaginally.

A preferred method of administering reboxetine Racemic is by oral dosage once or twice a day. It can also administer in doses of 2, 4, 6, 8, 10 or 12 mg / day or fractions of them. For example, appropriate administrations could be 4 mg in the morning and 2 or 4 mg in the afternoon or at night. In some patients, the ideal dose would be 3 to 5 mg in the morning and 3 to 5 mg in the afternoon. An expert doctor or psychiatrist can Determine the exact level of dosage. The ideal dose is routinely determined by an evaluation of clinical trials and the needs of specific patients.

According to the present invention, reboxetine racemic can also be administered as the free base or one of its pharmaceutically acceptable salts. The phrases "sales pharmaceutically acceptable "or" one of its salts pharmaceutically acceptable "refers to salts prepared to from pharmaceutically acceptable acids or bases, including organic and inorganic acids and bases as described previously. A preferred reboxetine pharmaceutical salt is the methanesulfonate (i.e., mesylate), which is prepared using acid methanesulfonic acid

The treatment or prevention of disorders above implies the administration of reboxetine in a manner and form that results in a reduction of the symptoms of disease or disorder As a rule, the symptoms that Children, teenagers and adults show are similar to each other. Therefore, as indicated above, the methods of Present invention are effective in treating patients Children, teenagers and adults.

Example

This example demonstrates the superior selectivity pharmacological and potency of a composition according to the present invention.

Rats were beheaded Sprague-Dawley weighing approximately 250 to approximately 300 grams (g), and the cerebral cortical tissue is removed immediately. The cerebral cortices were homogenized in nine volumes of medium each containing 0.32 molar sucrose (M), using a rotary breaker. The homogenate obtained is centrifuged at about 1,000 x g for about 10 minutes at about 4 ° C. A supernatant was collected and centrifuged more at approximately 20,000 x g for approximately 20 minutes at a temperature of approximately 4 ° C. A pellet of protein that was obtained from the centrifugation stages was resuspended in a Kreb's-Hepes buffer to result in a protein concentration of approximately 2 mg / ml buffer. The buffer was maintained at a pH of approximately 7.0 and contained: 20 mM Hepes; NaHCO3 4.16 mM; KH 2 PO 4 0.44 mM; NaH 2 PO 4 0.63 mM; 127 mM NaCl; 5.36 mM KCl; CaCl2 1.26 mM; and 0.98 mM MgCl2.

The protein / buffer suspension was introduced into 166 test tubes such that approximately 30 were added mug (10-6 g) to approximately 150 de of protein in each of the 166 test tubes (i.e. 80 tests per test  conveyor). The binding to the reuptake sites of the Serotonin and norepinephrine was determined as follows. The 3 H-norepinephrine synaptosomal reuptake is determined as follows. [3 H] citalopram were used approximately 1.4 nanomolar and [3 H] nixosetine approximately 1.9 nM to mark, respectively, the sites of reuptake of serotonin and norepinephrine. Union not specific was defined with 100 micromolar fluoxetine (µM) (for serotonin) and 10 µM desipramine (for norepinephrine). Be performed the incubation in a total test volume of 500 microliters (µl) for approximately 60 minutes (for serotonin) and 120 minutes (for norepinephrine). Both incubations were performed at approximately 25 ° C, and terminated by rapid filtration through a 48 cell collector wells through GFB filters (pre-soaked with approximately 0.5 PEI for approximately 4 hours) in 3 x 5 ml of ice-cold 200 mM tris-HCl, at pH 7.0. The perforated filters were placed in 7 ml minivials and the  radioactivity by means of a liquid scintillation counter.

The ability of reboxetine (that is, the racemic mixture of reboxetine (R, R) and (S, S)), reboxetine (R, R), and reboxetine (S, S) to join the reuptake sites of the norepinephrine and serotonin was evaluated in binding assays using the two radioligands, [3 H] citalopram and [3 H] nixosetine. The concentration of the compound of test required to inhibit 50% of specific binding in both reuptake sites (IC 50 values) was determined by Nonlinear least squares regression analysis. It has been made a conversion of IC_ {50} values into K_ {i} values using the Cheng-Prassoff equation that is presented to continuation:

K_ {i} = IC_ {50} / (1 \ + \ ([L] / [K_ {d} \ de \ L])),

wherein [L] is the concentration of radioligand used in nM, and K d is the binding affinity of L in nM. See YC Cheng and WH Prusoff, "Relationship Between the Inhibitory Constant (K_ {i}) and the Concentration of Inhibitor Which Causes 50% Inhibition (IC_ {50}) of an Enzimatic Reaction", Biochemical Pharmacology, vol. 22, pages 3099-3108 (1973).

The values of K_ {i} calculated according to Cheng-Prassoff equation are provided in the following table:

TABLE

Compound Reuptake of Recapture from Selectivity of K_ {i} from norepinephrine serotonin serotonin / norepinephrine (K_ {i} nM) (K_ {n}) Reboxetine (S, S) 0.23 ± 0.06 2,937 ± 246 12,770 Reboxetine (R, R) 7.0 ± 1.7 104 ± 43 fifteen Reboxetine 1.6 ± 0.6 129 ± 13 81

The data shows that racemic reboxetine it has a selectivity that favors 81 times the inhibition of norepinephrine reuptake on the inhibition of reuptake of serotonin.

Claims (5)

1. The use of racemic reboxetine, or one of its pharmaceutically acceptable salts, in the manufacture of a non-transdermal medicine for the treatment or prophylaxis of migraines 2. The use of claim 1, wherein the racemic reboxetine will be administered in an amount of 2 to 20 mg / day 3. The use of claim 2, wherein the racemic reboxetine will be administered in an amount of 4 to 10 mg / day 4. The use of claim 3, wherein the racemic reboxetine will be administered in an amount of 6 to 10 mg / day 5. The use of any of the claims above, in which the pharmaceutically acceptable salt of the Racemic reboxetine is methanesulfonate.